Ursodeoxycholic Acid Enhances the Antibacterial Activity of Colistin by Inhibiting MCR-1

Colistin is recognized as the “last line of defense” for the treatment of carbapenemase-producing “super-resistant” bacteria. However, the treatment of clinical bacterial infections has become more challenging due to the widespread prevalence of the novel resistance gene mcr-1 in multidrug-resistant pathogens. Currently, the use of natural compounds as novel adjuvants to colistin treatment is a safe, feasible, and promising approach compared to the high cost and unpredictability of developing novel antimicrobial drugs. Here, we identified a potential MCR-1 inhibitor, ursodeoxycholic acid, that may be used to treat infections caused by MCR-1-positive drug-resistant bacteria. In this study, checkerboard minimum inhibitory concentration assays demonstrated that ursodeoxycholic acid could reduce the MICs of colistin-resistant strains 4–64 times. Furthermore, a time-kill curve analysis, combined with disk diffusion testing and live/dead bacterial staining, demonstrated that ursodeoxycholic acid could effectively enhance the antibacterial activity of colistin, and when the concentration of ursodeoxycholic acid was lower than 512 μg/ml, it did not affect the normal growth of bacteria; thus, ursodeoxycholic acid imparts less selective pressure on bacteria and did not easily induce the emergence of drug resistance. In addition, through potential target prediction, molecular docking, RT-PCR analysis, membrane permeability detection, and scanning electron microscopy analysis, we demonstrated that ursodeoxycholic acid can form a complex with MCR-1, suggesting that UDCA may affect the activity of MCR-1. In addition, ursodeoxycholic acid combined with colistin was able to alter the electronegativity and permeability of the bacterial membrane, thereby disrupting the structural integrity of the bacterial membranes and significantly enhancing membrane damage–associated colistin activity. In summary, our findings indicate that the colistin/ursodeoxycholic acid combination may be a promising alternative approach for treating MCR-1-positive bacterial infections.